Response to National Institutes of Health Small Business Innovation Research (SBIR) Phase II Application for Grant- 1R43FD005345-01A1 Funding Opportunity Title : Response to National Institutes of Health Small Business Innovation Research (SBIR) Phase II Proposal for the Grant- 1R43FD005345-01A1 Solicitation Topic Code: FDA Phase I Contract # : 1R43FD005345-01A1 Agency : HHS Agency Tracking Number: : R43FD005345 Proposal Title : A Multiscale Simulation Toolkit for Computational Pharmacology of Trans/Intradermally Administered Compounds in Healthy and Diseased Population ABSTRACT Delivery of therapeutic drugs via the dermal route is a promising alternative to oral or parenteral delivery routes because dermal drug delivery systems (3DS) offer unique advantages such as controlled drug release over sustained periods for steady absorption into the systemic circulation, significant reduction in first-pass effects and gastrointestinal irritation, reduced dosing frequency and systemic toxicity, and better patient compliance. While less than twenty transdermal drugs have been approved in the U.S. since 1979, the number of generic drugs has steadily grown over the last three decades. Additionally, the market for intradermal delivery systems is also expanding. Accordingly, the market potential of 3DS, valued at ~$13B in 2005, is expected to reach ~$80B by 2024, with an annual growth rate of 8%. In response to this trend, a physiologically inspired simulation toolkit that can predict the clinical pharmacokinetic response and therapeutic effect of dermally administered compounds by optimizing dosage, formulation and administration scenarios (e.g., regimenting) can complement and accelerate drug development, clinical investigations and regulatory evaluation. To this end, the overall goal of this project is to develop and deliver a multiscale simulation toolkit for computational pharmacology of trans/intradermally administered compounds (CPDAC) in healthy and diseased skin population. During Phase I, we developed a model of healthy skin and linked it with a systems pharmacology model and predicted the dermal absorption and clinical pharmacokinetics of first generation (Gen- 1) transdermal systems (patches, creams, gels and ointments), and validated with clinical data. Going into Phase II, we will augment the scope of CPDAC by including additional Gen-1 transdermal systems, second and third generation (Gen-2 and 3) dermal drug delivery systems in healthy and diseased skin population. Specifically, we will develop: quantitative structure activity relationship (QSAR)-based generalized constructs to automate the action of chemical penetration enhancers (CPEs) on drug permeation, computational models of field-assisted iontophoresis (Gen-2) and microneedle-based intradermal drug delivery (Gen-3), which have not been attempted before. The models will be designed in a modular/parametric form to accommodate subject- specific physiology, user-defined fidelities of specific skin layers (0D-3D), embedded skin microvasculature. The models will then be integrated into a ?holistic trans/intradermal model?, which will then be linked to an advanced in vitro to in vivo correlation (IVIVC)-linked whole-body physiologically based pharmacokinetic model (PharmaLab CTS) for predicting the local and systemic pharmacokinetics of drugs, generics and cosmetics delivered from Gen-1/2/3 systems, in healthy and diseased skin population (e.g., psoriasis, eczema, acne and keratosis). In collaboration with our preclinical and clinical partners, the models will be systematically calibrated and validated at each stage of the development process toward delivering a robust, predictive and commercial quality CPDAC toolkit for end-user evaluation (as GUI to pharma, FDA and therapeutic product developers). 1